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Genome-wide association study of subclinical interstitial lung disease in MESA.

ABSTRACT: BACKGROUND:We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. METHODS:We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n?=?2,434), African American (n?=?2,470), Hispanic (n?=?2,065) and Chinese (n?=?702), as well as stratified by race/ethnicity. RESULTS:Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P?=?2.1x10-9) and within introns of SNAI3-AS1 (rs140142658, P?=?9.6x10-9) and D21S2088E (rs3079677, P?=?2.3x10-8). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n?=?1,959 participants from the Framingham Heart Study (P?=?0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n?=?228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P?=?0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P?=?0.001), ALCAM (P?=?0.03) and FOXP4 (P?=?0.046) were differentially expressed. CONCLUSIONS:Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.

SUBMITTER: Manichaikul A

PROVIDER: S-EPMC5437638 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genome-wide association study of subclinical interstitial lung disease in MESA.

Manichaikul Ani A Wang Xin-Qun XQ Sun Li L Dupuis Josée J Borczuk Alain C AC Nguyen Jennifer N JN Raghu Ganesh G Hoffman Eric A EA Onengut-Gumuscu Suna S Farber Emily A EA Kaufman Joel D JD Rabinowitz Dan D Stukovsky Karen D Hinckley KDH Kawut Steven M SM Hunninghake Gary M GM Washko George R GR O'Connor George T GT Rich Stephen S SS Barr R Graham RG Lederer David J DJ

Respiratory research 20170518 1

<h4>Background</h4>We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study.<h4>Methods</h4>We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hi ...[more]

PMID: 28521775

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Project description:RationaleObstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia.ObjectivesTo determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling.MethodsWe performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomographic imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) by polysomnography and high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) by computed tomography. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders.ResultsThe mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI was 8.4 events/h, and 32% had an oAHI greater than 15. After adjusting for demographics, smoking, and center, an oAHI greater than 15 was associated with a 4.0% HAA increment (95% confidence interval [CI], 1.4-6.8%; P = 0.003) and 35% increased odds of ILA (95% CI, 13-61%; P = 0.001). However, there was evidence that these associations varied by body mass index (BMI) (P for interaction = 0.08 and 0.04, respectively). Among those with a BMI less than 25 kg/m2, an oAHI greater than 15 was associated with a 6.1% HAA increment (95% CI, 0.5-12%; P = 0.03) and 2.3-fold increased odds of ILA (95% CI, 1.3-4.1; P = 0.005). Among those with a BMI greater than 30 kg/m2, an oAHI greater than 15 was associated with 1.8-fold greater odds of ILA (95% CI, 1.1-2.9; P = 0.01) but was not associated with HAA. There were no meaningful associations detected among those with a BMI of 25-30 kg/m2. Greater oAHI was associated higher serum SP-A and MMP-7 levels, particularly among those with a BMI less than 25 kg/m2.ConclusionsModerate to severe OSA is associated with subclinical ILD and with evidence of alveolar epithelial injury and extracellular matrix remodeling in community-dwelling adults, an association that is strongest among normal-weight individuals. These findings support the hypothesis that OSA might contribute to early ILD.

Dataset Information

Genome-wide association study of subclinical interstitial lung disease in MESA.

Publications

Genome-wide association study of subclinical interstitial lung disease in MESA.

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